Introduction

The human immunodeficiency virus (HIV) and tuberculosis (TB) are two of the major infections that continue to be global health threats. Efforts have been undertaken to combat these diseases, with global reports highlighting the urgency of the issue. Global reports indicated there were 1.5 million new HIV infections and 680,000 deaths from acquired immune deficiency syndrome (AIDS)-related causes in 2021 alone. However, substantial challenges persist. An estimated 27.5 million people are currently on antiretroviral (ARV) medication globally. Of the 377 million people living with HIV, an estimated 10.2 million are not currently on HIV treatment [1]. Until 2019, TB was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. While significant progress has been made, the number of patients newly diagnosed with TB between 2020 and mid-2021 in most of the high TB-burden countries was significantly below average compared to 2019. An immediate consequence of this can be observed in the number of TB deaths in 2020, estimated at 1.3 million people with an additional 214,000 deaths among HIV-positive people [2].

These two infections exert massive pressure on health care systems worldwide and even more so when combined due to an increase of resources needed to treat co-infected patients. The co-existence of these diseases presents unique difficulties, as HIV and TB have an interconnected relationship which causes severe adverse effects [2, 4]. Notably, HIV/TB co-infection prevalence is highest in the African region with southern Africa exceeding 50% of these cases. This indicates a substantial gap in testing and treatment for co-infected cases, as the amount of people diagnosed with TB that know their HIV status has decreased to 4.2 million [2].

To alleviate the disease burden, the World Health Organization (WHO) compiled a list of high-burden countries regarding global TB cases. While South Africa ranks 8th globally in terms of TB cases, accounting for 3.3% of the total global TB cases, it ranks 1st in HIV cases, with an estimated 7,800,000 people living with HIV—this accounts for 13% of the global HIV cases. In 2020, Africa accounted for a major 25% of the total global TB cases, with South Africa making up a substantial 13.2% of these. Africa was also reported as the region with the highest cases of HIV/TB co-infection (individuals infected with HIV and active TB), with South Africa contributing to an astounding 50% of these [1, 2]. Looking ahead to 2030, the WHO continues its resolute stance against TB through the “End TB Strategy”, which encompass a holistic strategy that includes (1) integrated patient-centred care to ensure equitable access for individuals affected by TB; (2) implementing inclusive policies and robust systems to address social determinants, strengthen health care systems, and provide financial protection; (3) driving innovation through intensified research; (4) mobilising communities for awareness and reducing stigma and discrimination; (5) fostering international collaborations for migrant populations; and (6) enhancing data-driven decision-making and adaptive strategies [2]. These interconnected elements collectively strive to eliminate the global burden of TB and promote a healthier world.

South Africa plays a pivotal role in advancing global efforts to combat TB by driving research, innovation in treatment, and facilitating clinical trials. This commitment extends to groundbreaking work on HIV preventative treatments, microbicide changes, and behavioural changes [5, 6]. The country has conducted several large-scale clinical trials and contributed research and resources to advance the development of an HIV vaccine [7]. Another standout achievement is the development of the Xpert MTB/RIF test, capable of detecting Mtb and rifampicin resistance [8]. Moreover, South Africa’s substantial genomic research on TB has unveiled genetic variations linked to increased TB susceptibility, providing important insights into its pathogenesis [9]. This dedication extends to TB vaccine research, exemplified by the South African Tuberculosis Vaccine Initiative (SATVI), which contributes to clinical trials worldwide [10].

The recent COVID-19 pandemic has introduced significant setbacks to the landscape of addressing HIV and TB in South Africa. The pandemic’s impact is multifaceted, leading to increased TB transmission within households due to isolation measures and instilling fear of seeking treatment outside homes, compounded by stigmatisation. This disruption is further emphasised by the negative stigma associated with COVID-19 contraction [11]. Notably, the pandemic has disrupted essential TB diagnostic and treatment services, significantly impeding overall progress as the COVID-19 pandemic took precedence [2]. Consequently, the strides taken in reducing TB mortality rates globally have suffered a setback due to the pandemic’s influence [11].

Historical context has profoundly shaped South Africa’s experience of the HIV and TB pandemics, underscoring the need to grasp their socio-economic underpinnings to formulate effective strategies for case management and significantly reducing mortality in the twenty-first century. Considering the historical trajectory of HIV and TB in South Africa, the progress made in their mitigation, and the persistent challenges faced, a clearer perspective emerges on the feasibility of attaining the WHO and United Nations (UN) Sustainable Development goals [12].

Methods: Search Strategy and Selection Criteria

This article reports on findings of several literature reviews about HIV and TB in South Africa. It also reports on the findings of the HIV and TB reports of the WHO and UN which are published each year. This article focusses on the co-infection of HIV and TB and its current prevalence in South Africa. However, few articles have evaluated the syndemic between these two diseases in South Africa specifically, and therefore, relevant articles from international literature were used as indications of what we may find through future research also in the southern African countries. Clinical trials and research included in this review were selected based on the criteria of whether the trial yielded successful results and if it was recently published.

References for this review included published results from the WHO TB reports and The Joint United Nations Programme on HIV/AIDS (UNAIDS) from 1997 to 2022. Other relevant articles were identified through Google Scholar by using terms “HIV”, “TB”, “Co-infection”, and/or “South Africa”. Relevant articles resulting from these searches were considered and cited in this manuscript. Only articles published in English were included.

A Short History of HIV in South Africa

South Africa has a unique history regarding its response to the HIV/AIDS pandemic. Although some decisions have been scrutinised, it is important to understand what led to these decisions in order to avoid the same pitfalls when future crises or pandemics arise.

The first recorded AIDS death of a South African was in 1981 [13]. Although this was more than 40 years ago, the country is still experiencing the repercussions from the array of decisions that resulted in unnecessary loss of life. In the 1980s, it was a widespread global belief that HIV/AIDS was a homosexual disease, resulting in a majority of the population not taking the necessary precautions to prevent the spread of HIV [14]. The Apartheid government at the time did, however, little to contest these claims. There were several untrue labels placed on individuals that had AIDS following the start of this pandemic which included homosexuals, migrant mine workers, and even haemophilic patients. Between 1983 and 1985, several haemophilic patients acquired HIV by receiving contaminated blood, leading to the assumption that haemophilic patients were at risk. Another belief arose from a 1986 survey done on mine workers in South Africa. During the survey, it was found that some of the participants (0.01%) had HIV and that they were coincidently all migrant workers. Following this survey, the government stated that immigrants were to blame for HIV, banning the entry of any HIV-infected migrant workers into the country [14]. Thus, the limited initial response to the pandemic can be attributed to the widespread beliefs that HIV/AIDS was a virus that only affected a specific type of person, namely homosexual men, haemophiliacs, and immigrant mine workers that entered the country [13, 14]. Since South Africa was ruled by Apartheid at the time, this misconception was advertised broadly to blame Black individuals and highlighted them as a threat to health, overall intensifying racial profiling [15]. This shifted the narrative to shaming the victims of the disease and blaming their infection on promiscuous behaviour [14].

In 1994, South Africa had its first democratic election during which Nelson Mandela was elected. Although this brought hope that the new government would dismantle racial inequalities and the stigma around HIV/AIDS, the pandemic still did not receive adequate resources and attention amidst all the new changes happening in the country [13]. In the following few years, the HIV mortality rate proceeded to surge [16] despite a very ambitious HIV/AIDS campaign that was outlined at the start of Nelson Mandela’s presidency. Despite making headway, the programme ultimately fell short of expectations by 1998 [16].

The year 1999 was another turning point in the HIV pandemic with the election of Thabo Mbeki as president, who appointed Dr. Manto Tshabalala-Msimang as Minister of Health [17]. Tshabalala-Msimang questioned whether HIV caused AIDS and advocated beetroots, lemon, and garlic instead of ARVs for South Africans [18]. Based on advice received at the time, and the influence of other denialist advocates such as Peter Duesberg (a German–American molecular biologist and professor at Berkeley), South Africa’s new president did not believe that HIV causes AIDS but rather socio-economic factors such as poverty. He sent a letter to world leaders to convince them of his belief. The misinformation kept piling on with the government, spearheaded by Tshabalala-Msimang, which delayed ARV roll-out due to insinuations that they were ineffective and toxic. Eventually, in 2002, the South African high court ordered the production and roll-out of ARVs [17]. Nonetheless, Tshabalala-Msimang continued to spread misinformation and proceeded to promote alternative treatments—these were not scientifically proven and were merely based on nutrition and palliative care. It is no surprise that her unsupported claims and promotion of “African treatments” afforded her the name “Dr. Beetroot” and continues to be an embarrassing memory of South Africa’s HIV past [19]. By 2006, mortality exceeded the number of new HIV infections, largely due to the slow roll-out of an antiretroviral therapy (ART) programme [14].

In 2009, Jacob Zuma was elected as president of South Africa. AIDS activists were sceptical about his appointment because of the controversial public statements [20] he made about HIV-positive women, i.e. that “taking a shower” would cut the risk of contracting HIV infection. However, the president left the denialistic claims of former president Thabo Mbeki behind and made progress in combatting the AIDS pandemic [17]. Since then, South Africa has made headway in achieving its goals to improve HIV mortality rates [1]. The current president, Cyril Ramaphosa, was elected in 2019 and has regarded the science behind the HIV/AIDS pandemic, which in turn allows him to make progress towards the goal to end the pandemic in South Africa [1, 21]. Although the current COVID-19 pandemic has taken a significant amount of South Africa’s resources that could have been spent on the HIV pandemic, the future seems promising considering the proactive response of President Rhamaphosa over the past 3 years of his term. This includes the call for increased treatment of HIV-positive individuals with ART and an overall positive, proactive approach towards HIV treatment [22, 23].

Upon evaluating the population percentage growth of South Africa in relation to the total HIV cases during the span of South Africa’s presidencies from 1990 to 2021 (see supplementary material; Fig. S1), it becomes evident that despite the continuous population growth, the rise in HIV cases within the country has been disproportionate. The gap between the overall population of South Africa compared to the amount of HIV cases started to reduce between 1994 and 2002, indicating increased effort to combat the disease with ARV roll-outs as these roll-outs increased over the following years. A slight spike in HIV cases reported in 2020 is possibly linked to the COVID-19 pandemic. After 2020, it was expected that the amount of HIV cases would continue to increase. However, data from the WHO 2022 report indicates there was a decrease in the percentage of total HIV cases from the previous year, with 2020 having a 4% increase from the previous year, and 2021 having a 3% increase from the previous year. Therefore, although the total amount of HIV cases in 2021 still increased from the previous year, the percentage increase was less comparatively. According to the UNAIDS 2022 update report, the global response towards the HIV crisis has been set back due to several global crises such as the COVID-19 pandemic that the world had to combat. Why then has the percentage of total HIV cases in South Africa not increased from the previous year?

The answer quite possibly lies in looking closer at the spike of HIV cases in 2020 (Fig. S1). In 2020, the percentage increase of HIV cases is the highest that it has been in 10 years. This disruption in the trend would suggest that the effects of the global COVID-19 pandemic were already visible in 2020, with the decrease in HIV cases shown in 2021 reflecting the increased knowledge and efforts in combating the COVID-19 pandemic [24], which had subsequently affected the HIV epidemic. The first roll-out of vaccinations for COVID-19 was administered at the beginning of 2021 in South Africa.

A Short History of TB in South Africa

Although TB has less political agendas attached to it, it is known as the “disease of poverty” in South Africa [25]. The WHO has published an annual global TB report since 1997 in which the prevalence, progress, and future goals towards the eradication of TB worldwide are discussed. As one of the countries with the highest amount of TB cases annually, South Africa is included in every report. Why does TB have such a foothold in the country, and what conditions in South Africa contribute to the high disease prevalence in poverty-stricken regions?

TB was first introduced to South Africa in the seventeenth century when European immigrants or colonists arrived in the country [14]. An interesting development led to the rapid spread of TB among the Black population of South Africa following this initial introduction. In the nineteenth century, South Africa began its explosive development of its mining industry. The conditions in the mines were grim with poor working conditions including being overcrowded, workers receiving low nutritious meals, and inhaling silica dust regularly, which contributed to the susceptibility and rapid spread of TB under these workers [14, 26]. It is proposed that the oscillatory movement of these mineworkers between their work and the rural communities that they lived in, which possessed minimal medical resources, majorly contributed to the spread of the disease [14].

In the twentieth century, TB cases rapidly and noticeably rose in South Africa, with a particular resurgence in the late 1990s [14]. During this period, the Apartheid government spent the larger portion of the health care budget on areas where the White population resided although they were the minority. When analysing the per capita expenditure of different areas, the predominantly “White living areas” were given almost four times the amount of per capita expenditure for health care compared to “Black areas” [27]. The lack of adequate health care provided by the government only fuelled the spread of TB in a time when it was critical to face the threat of TB head-on. Arguably, by 1994, when the Apartheid government was abolished, the damage was already done, and TB posed a much greater threat to the country than initially anticipated.

In 1997, the National Tuberculosis Programme (NTP) was established to actively address the failing primary health care systems in place meant to deal with the TB endemic. One of the biggest milestones of this programme was the implementation of the directly observed treatment short-course (DOTS), which immensely strengthened the TB treatment programme [28]. Although this was a step in the right direction, the potential gain of TB control was less than expected, with major progress being countered by the maturing HIV pandemic which saw a rapid increase during this time [14]. However, the initiatives under the NTP continued ahead, not deterred by the apparent lack in progress.

In 1999, the WHO introduced DOTS-Plus, a programme launched to address the growing concern of multi-drug resistant (MDR) TB. This programme was aimed at building upon the five elements of DOTS (i.e., political commitment, microscopy services, drug supplies, surveillance and monitoring systems and use of highly efficacious regimens, and direct observation of treatment) while considering second-line anti-TB drugs, specifically the need to use them in resource-limited settings. The first pilot projects for DOTS-Plus were launched in 2000, and by 2006, these pilot projects showed significant evidence that demonstrated MDR TB can effectively be treated using DOTS-Plus [2]. The WHO’s TB guidelines were subsequently endorsed, and further treatment facilities were established for MDR TB by the NTP in South Africa. The DOTS-Plus programme was, however, only launched in South Africa in 2002 [29]. Since 2003, there were several more initiatives and milestones reached under the NTP. A discussion of these falls beyond the scope of this review, but the authors recommend the thorough review of Churchyard et al. [28], should the reader be interested.

Despite the introduction of the MDR TB guidelines, MDR TB and extensively drug-resistant (XDR) TB completely took over the nation, increasing the national emergency that TB posed. In 2007, a study was done that identified XDR TB cases in all nine provinces of South Africa, highlighting the extreme prevalence of drug-resistant TB strains. Both the DOTS and ART programmes are threatened by these drug-resistant TB strains due to the exclusion of first-line TB medication when patients are resistant to isoniazid and rifampicin [14, 30], the main drugs used for treating drug-susceptible TB. Second-line TB medication, used for treating drug-resistant TB, is not ideal as these medications place a huge burden on the liver, and side-effects often include liver inflammation, jaundice, joint pain, and indigestion. These side-effects in turn may ultimately lead to patient non-adherence [31, 32].

Since 2007, progress has been made towards reducing the number of TB deaths in South Africa, although certain setbacks were encountered [2]. South Africa’s first-ever prevalence study was conducted in 2018. This was a major advancement as it enabled the WHO to conduct more accurate global estimates and to provide important estimates of the burden of TB in South Africa. It also brought new information on health-seeking behaviour of patients to light [33].

When regarding the history of both HIV and TB, although they are two separate diseases of viral and bacterial descent, respectively, they have a highly interconnected relationship, posing a deadly threat to high-burden countries like South Africa. The control of these pandemics is fundamental to the future economic growth and political progress of the country [34]. The historical conditions, specifically the impact of Apartheid, have shaped and defined the nature of HIV and TB pandemics in South Africa as we combat these diseases in the twenty-first century. Although major progress and headway have been made since the first TB case in South Africa, high TB case prevalence and mortality rates continue to be a concern in the country. If the end of the HIV and TB pandemics is to be achieved, a better national response is required from not only the country’s health minister but also a unified effort between researchers and health care professionals alike.

When comparing the difference between the number of TB deaths in HIV-negative people compared to those in HIV-positive people in South Africa (Fig. S2), the detrimental effect of HIV/TB co-infection is evident. HIV and TB attenuate each other as the number of TB deaths in HIV-positive people far exceeds the number of TB deaths in HIV-negative people. Therefore, it is evident that that relationship between HIV and TB should be investigated further.

The Co-dependent Relationship Between HIV and TB

Africa has the highest rate of HIV/TB co-infection in the world, with a large contribution stemming from South Africa. When two diseases combine, they form an even deadlier syndemic, referring to exacerbated health consequences of the biological interactions observed in multiple individuals within a population when both are present [35]. The deadly consequences related to simultaneous infection of a host have been referred to as “the cursed duet”.

In newly HIV-diagnosed patients, TB is the most common presenting illness and the most prevalent opportunistic disease among people living with HIV [36]. It was reported that among the total worldwide incident cases of TB, 8% of these were people living with HIV. In Africa, the proportion of TB cases co-infected with HIV was the highest as reported in 2020. Not only are HIV patients more susceptible to contracting TB, but it also lowers treatment success rates. The success rate among co-infected patients is 77% compared to 86% (for first-line TB treatment regimens) in those with only TB [2]. Contributing to the low treatment outcomes, is the rapid development of drug-resistant strains which complicates treatment [36]. The comparison between HIV and TB deaths in South Africa can be seen in Fig. 1. This figure depicts the relationship between the amount of HIV and TB deaths divided by their subsequent incidences expressed as a percentage. This percentage illustrates the correlation between the mortality rate and the incidence of each disease, revealing the number of individuals who succumb to the infection. This percentage has remained relatively steady and experienced a significant decrease since 2020. An important contributing factor to note is that proper treatment for HIV can substantially extend individuals’ lives, which can contribute to this figure [2].

Fig. 1
figure 1

The relationship between the total deaths to deaths divided by incidence percentage, for HIV and TB in South Africa. Total TB deaths are indicated with a green line, TB deaths vs incidence percentage is indicated with a dotted blue line, total HIV deaths are indicated with a yellow line, and the HIV deaths vs incidence percentage is indicated with a dotted orange line

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Deaths due to both HIV and TB have been decreasing from around 120,000 in 2012 to around 83,000 for HIV (orange line in Fig. 1) and 61,000 for TB (green line in Fig. 1) in 2020. It is, therefore, clear that the prevention of TB deaths has been more successful than the prevention of HIV deaths over the last 8 years in South Africa. This is illustrated by the death divided by incidence percentage dotted lines in the graph. TB incidence has decreased to around 18% in 2020, whereas HIV incidence has been rising steadily to around 30% in 2020. Thus, in the case of HIV infections, preventative treatment is relatively successful whereas treatment of the AIDS patients is not that successful. This can also be seen in the number of HIV infections per 1,000 people that has been reduced from 8.4% in 2012 to 4.6% in 2020.

The amount of total HIV and TB deaths in South Africa has decreased from 2020 to 2021. Taking the COVID-19 pandemic into account, it can be argued that since HIV-positive individuals’ immune systems are more vulnerable, these individuals have a higher chance of contracting COVID-19 and subsequently their death was instead recorded as such and not exclusively an HIV death. The data and records of the causes of death might thus be affected by a global health threat such as the COVID-19 pandemic.

But what causes HIV and TB to have such an intricate relationship and how do they potentiate each other? Although we do not understand the detailed mechanisms of this interaction [4], HIV and TB enhance each other causing increased and accelerated deterioration of immunological functions, which, when treated poorly, causes an early death for the patient. HIV has been identified in high-burden countries, such as South Africa, as the most important risk factor to develop active TB, and in patients with latent TB, it increases the susceptibility to primary infection or the risk of TB reactivation [37]. As a patient’s CD4 + T-cell count decreases, their probability to progress to active TB increases [36]. This increased susceptibility of HIV-infected patients to TB can greatly be attributed to two main mechanisms, namely (1) the increased reactivation of latent TB, or (2) the increased risk of contracting Mtb. The possibility of both situations being present suggests that these disease states should be closely monitored [2]. There are several features of patients with HIV that make them more susceptible to TB infection. One of the main features of HIV/AIDS is the immunosuppression that causes a loss of CD4 + T-cells. However, the underlying mechanism of this increased susceptibility is clearly more complicated as it has been shown that TB susceptibility increases soon after HIV infection, which means the CD4 + T-cell count is not the only culprit [2, 38]. Another feature of HIV/AIDS is the sustained immune response induced by the host since a prolonged immune activation leads to an enhanced disease progression, therefore making these patients more susceptible to TB [38]. These mechanisms are complex and poorly understood, necessitating further research to enhance comprehension for improved diagnostics and treatment approaches in the HIV/TB co-infected disease state, including the extent to which disease attenuation occurs and the associated metabolic alterations [4, 39]. However, conventional methodologies employing labour-intensive biochemical assays [39] have demonstrated alterations in net protein balance [40], hypoalbuminemia [41], and similar body composition shifts [42] in co-infected individuals relative to individuals with HIV infection or TB alone. In 2023, a pioneering study explored the serum metabolic profiles of healthy controls, untreated TB-positive patients, untreated HIV/TB co-infected patients, and HIV/TB co-infected patients on ART. This investigation unveiled substantial shifts in lipid and protein metabolism, alongside translocation of microbial products from the gut to the bloodstream. The findings imply a synergistic amplification of TB by HIV, contributing to increased inflammation, oxidative stress, ART-induced mitochondrial damage, and detrimental effects on gut health, thereby influencing energy availability. Although ART partially counteracts these trends in co-infected patients, further research is warranted to fully comprehend these changes and their implications [43].

From 2012 to 2020, total TB mortality in South Africa has been showing an overall declining trend (grey line in Fig. 2). From 2016 to 2020, the TB death percentage based on the total TB deaths reported has been declining for HIV-positive individuals with TB (orange line) compared to HIV-negative individuals (blue line), which could indicate that HIV has been better managed in South Africa since 2016.

Fig. 2
figure 2

TB mortality as a percentage of total TB mortality for HIV-positive (orange line) and HIV-negative (blue line) subjects, with total TB mortality numbers (grey line), shown from 2012 to 2021

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Social and Biological Dynamics in South Africa that Contribute to HIV/TB Co-infection

The intertwined histories of both HIV and TB in South Africa have significantly influenced the syndemic challenges in the country today. However, specific social and biological dynamics play pivotal roles in perpetuating the spread of these diseases despite advancements in medical technology. TB has often been named as a “social disease” or “disease of poverty”, alluring to the living conditions and communal behaviours that contribute to its propagation [44]. Given the substantial proportion of South Africans living in poverty [45], conditions conductive to HIV and TB transmission prevail. Several studies underscore overcrowding as a notable driver of increased TB transmission [46, 47]. Close-knit living in informal settlements escalates the risk of both HIV and TB dissemination [48]. Furthermore, prevailing social challenges include inadequate food security, limited health care access, substandard living conditions, and a lack of disease awareness [38, 44]. The absence of proper education and treatment engagement in these communities exacerbates disease propagation. The intertwining of impoverished circumstances cultivates an environment that promotes HIV and TB transmission [38]. Moreover, the dual burden of social stigmatisation associated with HIV and TB, which can manifest as fear of discrimination or isolation, as well as misconceptions about the diseases, impedes individuals in communities from seeking essential treatment [49]. Effectively addressing disease management may necessitate an integral focus on rectifying the social and biological contexts within South African communities, a vital step towards significant progress.

Current Progress Supporting South Africa’s Efforts Against HIV and TB

South Africa has recognised the significance of social dynamics in the battle against HIV and TB. Numerous campaigns have been undertaken to confront the stigma and hurdles encountered by communities when seeking treatment. An example of such an effort was initiated by the South African National AIDS Council (SANAC), aiming to counteract persistent social perceptions that continues to fuel stigma and discrimination against people living with HIV. The campaign featured the slogan “I can’t change my HIV status but I can change my attitude” [50]. Subsequent to this, multiple other campaigns have been introduced in South Africa to educate and destigmatise these diseases within communities.

South Africa has played a significant role in global HIV research. Notably, it has contributed to HIV preventative treatments, including pre-exposure prophylaxis (PrEP). A recent study in South Africa examined the initiation and adherence to oral PrEP in a group of young women, providing crucial insights on expanding HIV prevention options for this vulnerable group in a high-burden HIV country like South Africa [51]. Further research has also focused on microbicide and behavioural changes [5, 6]. South Africa has been a site for several large-scale clinical trials of HIV prevention methods with a total of 21 clinical trials initiated up until 2020 [52], and even more being initiated since then. Notable successful trials include the HPTN 052 trial, which demonstrated the remarkable efficacy of ART in safeguarding against sexual transmission of the HIV virus. This ground-breaking study revealed that initiating ART in HIV-infected individuals before severe immune system compromise led to a substantial 93% reduction in HIV transmission. These findings underscore the enduring and dependable protective benefits of ART in preventing the spread of the virus through sexual contact [53]. Another impactful clinical trial was the ASPIRE trial, a phase III randomised, double-blind, placebo-controlled study evaluating the efficacy of the dapivirine vaginal ring. This study was conducted across 15 sub-Saharan African sites, including South Africa [54]. South Africa also contributed extensively to HIV treatment research over the years, exploring the impact and adherence of South African cohorts to ART administration [55]. South Africa has taken crucial steps to identify important barriers relating to treatment regimes, proposing several strategies aimed at enhancing treatment administration in the country to improve outcomes [56,57,58]. Efforts towards HIV vaccine development are being pursued through the South African AIDS Vaccine Initiative (SAAVI), established in 1999 in collaboration with government, ESKOM, and the Medical Research Council [59]. South Africa has a high prevalence of both HIV and TB, and co-infection research, considering their metabolic impact, is being thoroughly researched in the country. A recent review examined the complex metabolic effects of HIV and TB and proposed several future objectives [4]. While a recent HIV vaccine trial, Mosaico phase III, failed in preventing HIV [60], the fight against HIV in South Africa continues unabated. Promising trials for the M72/AS01E TB vaccine are ongoing in South Africa in 2023 [7], and an innovative approach using allogeneic haematopoietic stem cell transplantation has shown success in curing HIV, with the involvement of Honorary Professor, Dr. Monique Nijhuis [61].

In combating TB, South Africa has made significant contributions, both scientifically and financially. Notable milestones include the development of the Xpert MTB/RIF test, which can detect Mtb and rifampicin resistance [8]. South Africa participated in a multi-country study evaluating the diagnostic accuracy of this test, collaborating with the Foundation for Innovative New Diagnostics (FIND) [8, 62]. The active participation of the country in this study, along with several other studies conducted by South African researchers, has played a vital role in the successful roll-out of this test. Notably, Professor Nicol and fellow researchers ascertained the accuracy of the test for diagnosing pulmonary TB in a South African Hospital [63]. Numerous clinical trials conducted in South Africa have contributed to TB research, including a landmark clinical trial by the Aurum Institute that demonstrated the efficacy of a shorter, simpler TB regime [64]. Significant genomic research on TB has also been conducted in South Africa, identifying genetic variations that increase susceptibility to TB and providing important insights into the pathogenesis of the disease [9]. The country has shown immense dedication to TB vaccine research through SATVI, contributing to clinical trials worldwide [10]. Notably, in December 2022, the WHO implemented a new all-oral 6-month treatment regimen for drug-resistant TB in South Africa, showing promising results [65]. The Deputy President of South Africa has launched a National Strategic Plan (NSP) to combat HIV and TB, emphasising breaking down barriers, ensuring equitable and equal access to HIV and TB services, building resilient health care systems, and establishing revitalised, inclusive, and accountable institutions [66]. This plan also acknowledges the impact of pandemics, such as the COVID-19 pandemic, on the fight against HIV and TB, highlighting the need to address burdens caused by such outbreaks. However, it is important to address underlying social economic challenges before the country can achieve the newly outlined goals of the NSP [67,68,69].

While South Africa is actively striving to combat both HIV and TB, the numerous clinical trials and research initiatives, while crucial in the fight against these diseases, do not adequately address the unique social barriers within South Africa that impede progress. The NSP acknowledges these barriers and delineates a well-structured strategy for achieving its four primary goals. However, despite the commendable efforts, there are areas where the practical implementation of these strategies faces challenges. South Africa’s history of economic challenges, corruption, and political turmoil presents significant obstacles to achieving the NSP’s goals [70]. The South African health sector exhibits a range of corrupt practices, including bribery, theft, and subpar service quality [71]. International research has indicated that in underdeveloped countries, corrupt practices are experienced by up to 80% of the population within the health sector [72]. With South Africa’s national elections coming up in 2024, the successful implementation of the NSP by the current Deputy President may encounter further obstacles in the coming years.

Adding Fuel to the Fire

It is evident that the syndemic of HIV and TB has been a major burden for South Africa for a very long time, which was worsened with the recent COVID-19 pandemic. One needs to consider the specific aspects that have contributed to the COVID-19 pandemic adding fuel to the fire, as well as their influence on future progress towards ending HIV and TB.

The WHO 2021 global report estimated that 1.4 million fewer people received care for TB in 2020, a 21% reduction compared to the previous year. The decrease is proposed to be caused by COVID-19-related disruptions such as lockdown implementation and the subsequent difficulty in delivering medicine and administering treatment with restricted access to clinics, hospitals, or treatment centres. Reduced accesses for TB diagnosis and treatment have been one of the biggest effects of COVID-19, ultimately leading to increased TB deaths. TB case detection and reporting have also been negatively affected as COVID-19 case detection and treatment have taken precedence. Several specific disruptions also impacted TB detection, specifically the overall health system capacity being reduced, reduced ability of people seeking health care services during national lockdowns being put in place, fear of contracting the COVID-19 virus during clinic visits, or stigmas associated with symptoms that are similar between TB and COVID-19, making people less willing to report their symptoms [2].

The HIV pandemic, specifically in South Africa, was also severely impacted by the COVID-19 pandemic. There was a 50% decrease in HIV testing and ART initiation at the beginning of the COVID-19 lockdown, which only marginally increased over the following months [73]. Different aspects of the COVID-19 pandemic have contributed negatively towards the progress of ending HIV. Dorward et al. [73] suggested a paucity of personal protective equipment, space for physical distancing in clinics, reduced opening times of clinics, and staff being redeployed from HIV testing and care to COVID-19 response activities played a crucial role in deterring HIV care. These additional challenges posed by COVID-19 added stress to a country that also faces severe poverty and issues with overall access to clinics in rural communities. A major challenge for South Africa currently is to reverse the effects COVID-19 had on ending both HIV and TB. The future WHO and UNAIDS reports might shed more light on the impact that COVID-19 had on these two diseases; however, the preliminary data already hints at major setbacks in both the fight against HIV and TB.

When considering South African’s TB deaths relative to the reported incidences, and comparing it to that of HIV, for the period of 2012 to 2021, a predicted future relationship can be determined (Fig. S3). If the current trends are followed, the TB number will be higher than expected in 2022/2023, which might reflect the impact of COVID-19 and the overall increase in death experienced by the country. It might, however, still be too soon to see the effects of COVID-19 on HIV as the WHO predicts that 2022 figures will reflect this effect better.

Prevalence Studies and Reliability of Data

Prevalence studies give an accurate measurement of disease burden in a population. These studies are of great importance to governments, health professionals, policymakers, and the public sector of a country as they report on the development of diseases and the success of health care delivered in an attempt to stop the disease from spreading [74]. Before 2020, there had not been any public data available reporting on TB prevalence in South Africa, despite the WHO strongly urging South Africa to conduct an internal prevalence study since 2008. Thus, the data that the WHO uses to compile annual estimates for South Africa is greatly based on modelling exercises. This means that the reported estimates from the WHO are unreliable as the data is based on clinical reports rather than actual data provided by the country [33]. To understand the true burden of TB in South Africa, and provide realistic estimates, a prevalence study was finally initiated in 2018 and published in 2021 [75]. The results showed that 737 new TB cases were reported in South Africa, in 2018, which is significantly higher than the number of new cases reported by the WHO, which was 520 cases [75, 76]. Limitations of the prevalence study worth mentioning include (i) the performance of the Xpert Ultra tests used for diagnosing patients, as various false positive results were produced and the data was subsequently adjusted and conservatively amended to account for this; (ii) the participation rate of the study was lower than expected with an overall participation of only 66.1%; (iii) the HIV status of the participants was based on self-reporting; and (iv) only certain participants were eligible for sputum examination [75]. Nonetheless, the overall impact of this study is overwhelmingly positive, as it provides valuable data that the WHO can use to improve their reporting on the TB prevalence in South Africa as well as supplying important cohort information between sub-groups such as the prevalence of TB in male and female participants of different ages. This prevalence study also sets a good precedence for future TB studies in South Africa.

The Human Sciences Research Council (HSRC), however, started conducting HIV prevalence studies in South Africa in 2002, followed by another five in 2005, 2008, 2012, 2017, and 2022. These studies are done in the form of national household surveys and are essential for supplying accurate HIV statistics for South Africa. However, this type of survey has drawbacks such as the exclusion of certain groups, e.g. children younger than 2 years old who may have been infected through mother-to-child transmission, as well as persons living in institutions like prisons, military barracks, and boarding schools. Of note is the much higher HIV prevalence in South Africa determined by the HSRC compared to early estimates by UNAIDS, as reported in 2018, which can be seen in Fig. 3. The more recent estimates made by UNAIDS in regard to HIV prevalence in South Africa is, however, more in line with HSRC statistics implying that UNAIDS have considered and adjusted their estimates in recent years to be more accurate [77]. Entities that report on global data, such as the WHO and UNAIDS, have certain criteria for data collection from various countries that are used to compile important estimates for annual reports. Reporting agencies and other sources such as hospitals and clinics within countries submit their yearly data, which is then analysed using specific software programmes. Since a country’s entire population cannot be tested for HIV or TB, only a portion of the population is selected, and estimates are made based on the selected data produced by the group. When countries conduct their own prevalence studies and population-based surveys as previously mentioned, these estimations can be adjusted to realistic data for accuracy, which aids in ending these pandemics.

Fig. 3
figure 3

Total HIV cases in South Africa as reported by the UNAIDS (blue bars) compared to the total HIV cases in South Africa as reported by the HSRC (orange bars), which is a South African internal study

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Are the “End TB” and “End HIV” Goals Out of Reach?

As mentioned previously, the WHO has set targets for ending TB. One of the main goals is to reduce the absolute number of TB deaths by 90% by the year 2030. The number of TB deaths (including HIV-positive and HIV-negative cases) in South Africa has not been declining linearly over the years (Fig. S4). Following the latest data from 2021, if the TB cases are to decline with 90% by 2030, a strengthened control approach is urgently needed to reach the 2030 goal. Similarly, the number of AIDS-related deaths among the South African population has been declining steadily over the years. If the same goals are to be applied to the number of AIDS-related deaths in South Africa, the goal would be a 90% reduction in the death toll by the year 2030. Considering current trends (Fig. S4 and Fig. S5), achieving the 2030 goal is highly unlikely—unless an immense, strengthened effort is made and maintained.

The WHO also provides more detailed goals to encourage the fight against TB. Figure 4 illustrates the TB death reduction goals set by the WHO (represented by the grey dots) for 2020 (35% reduction), 2025 (75% reduction), 2030 (90% reduction), and 2035 (95% reduction). Although South Africa seems to be on the right track in reducing TB mortality, the country will have to strengthen its overall effort in combatting TB to achieve the WHO goals.

Fig. 4
figure 4

New TB cases (blue line) and total deaths (orange line) in South Africa, including the World Health Organization’s global targets (grey line) for 2020, 2025, 2030, and 2035. The new case targets are indicated with a yellow line

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The goals set by the WHO are meant to motivate countries to end the TB pandemic. As previously mentioned, the WHO’s “End TB Strategy” for 2030 involves a comprehensive approach, including patient-centred care, inclusive policies, innovative research, community mobilisation, global collaborations for migrants, and data-driven adaptive strategies to combat TB. Although these goals are usually accompanied by several suggested strategies on how to achieve them [2], they are not personalised to specific counties. Since each country faces its own set of challenges, social dynamics and stigmas should be addressed first before the ultimate goal of ending TB can be achieved.

Although South Africa has made progress in the reduction of TB incidences with the country's research and NSP implementation, these might not be enough to achieve the “End TB” goals. When considering similar efforts made by the country between 2015 and 2020, the goals were not met. The aim was to reduce TB incidences by 20%, and only 9% of the incidences were reduced by 2020. The death rate was also aimed to be reduced by 35%, and only a 14% reduction was achieved by 2020 [78]. It is thus evident that the long-term "End TB" goals will not be achievable if the problems at hand faced by South Africa are not dealt with first.

Conclusion

The complex interplay of history, society, and health crises has moulded the landscape of HIV and TB in South Africa, impacting the country’s battle against these stubborn pandemics. Apartheid’s shadow still looms, contributing to a disproportionate burden on vulnerable groups and a complex co-infection dynamic. Although progress has been achieved through research and interventions, the persistent high disease rates highlight the urgency of the challenge. The recent COVID-19 pandemic has further complicated matters, undoing previous gains and revealing health care system vulnerabilities. Yet, South Africa’s commitment to accurate data via prevalence studies offers hope for informed strategies. Achieving the ambitious “End TB” and “End HIV” goals demands more than data; it requires a coordinated approach, strong health systems, fair access, and robust institutions. While the journey ahead is challenging, past accomplishments driven by resilience demonstrate progress is possible. Confronting historical injustices, overcoming stigmas, and advancing co-infection research require collective effort. Through shared determination, South Africa’s pursuit of a healthier, fairer future reflects its resilience and dedication to its people’s well-being.